title: MicroRNA187 overexpression is related to tumor progression and determines sensitivity to bortezomib in peripheral T-cell lymphoma.
abstract: MicroRNAs (miRs) are involved in tumorigenesis by regulating tumor suppressor genes and/or oncogenes. MiR187 was overexpressed in peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and associated with high Ki67 expression, elevated lactate dehydrogenase, advanced International Prognostic Index and poor prognosis of patients. In vitro, ectopic expression of miR187 in T-lymphoma cell lines accelerated tumor cell proliferation, whereas treatment with miR187 inhibitor reduced cell growth. MiR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERK) and AKT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib. Bortezomib inhibited T-lymphoma cell proliferation by downregulating miR187, dephosphorylating ERK and AKT and degrading MYC. In a murine xenograft model established with subcutaneous injection of Jurkat cells, bortezomib particularly retarded the growth of miR187-overexpressing tumors, consistent with the downregulation of miR187, Ki67 and MYC expression. Collectively, these findings indicated that miR187 was related to tumor progression in PTCL-NOS through modulating Ras-mediated ERK/AKT/MYC axis. Although potentially oncogenic, miR187 indicated the sensitivity of T-lymphoma cells to bortezomib. Cooperatively targeting ERK and AKT could be a promising clinical strategy in treating MYC-driven lymphoid malignancies.
authors.affiliation: 1] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [2] Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: Z-X
authors.initials: ZX
authors.lastname: Yan
authors.affiliation: Department of Pathology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: L-L
authors.initials: LL
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.
authors.forename: K
authors.initials: K
authors.lastname: Xue
authors.affiliation: Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.
authors.forename: Q-L
authors.initials: QL
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: UMR-S728, Laboratoire de Pathologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Romero
authors.affiliation: UMR-S728, Laboratoire de Pathologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Leboeuf
authors.affiliation: UMR-S728, Laboratoire de Pathologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Janin
authors.affiliation: 1] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [2] Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: 1] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [2] Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [2] Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: W-L
authors.initials: WL
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D011719:Pyrazines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C571843:MIRN187 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases